Lung cancer is the leading cause of cancer death in the United States and worldwide. Cigarette smoking causes approximately 90% of lung cancer. Despite anti-smoking campaigns over the past 40 years, over 45 million (22%) adult Americans are still current smokers. The development of a viable chemoprevention strategy targeting current smokers potentially could decrease lung cancer mortality. Previous studies have shown (1) that the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK) is a major lung carcinogen in tobacco smoke, (2) that 2-phenethyl isothiocyanate (PEITC) is a potent inhibitor of NNK-induced lung carcinogenesis in rats and mice, (3) that the mechanism of this chemopreventive effect in rats is inhibition by PEITC of NNK's metabolic activation by a-hydroxylation in the lung leading to significantly increased urinary levels of the NNK metabolites 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Glucs). Furthermore, in smokers, consumption of watercress, a rich source of PEITC, increased urinary excretion of NNAL plus NNAL-Glucs, a marker of NNK detoxification, by 33%, consistent with the results of the animal studies. Observational epidemiological studies have demonstrated that dietary intake of cruciferous vegetables or isothiocyanates is associated with a reduced risk of lung cancer. The protective effect is confined to individuals with glutathione S-transferase (GST) M1 null-null or GSTT1 null-null genotype, and is particularly evident among those with the null genotypes of both GSTM1 and GSTT1. No protective effect was found among subjects with GSTM1-positive or GSTT1-positive genotype. The ultimate goal of our proposed research is to gain a full understanding of the mechanisms underlying the inhibitory effect of isothiocyanates on lung carcinogenesis in humans. The primary aim of this proposal is to assess, via a placebo-controlled cross-over design, the effect of PEITC supplementation (at 40 mg per day for one week) on changes of NNK metabolism in 80 smokers, who possess both the GSTM1 null- null and the GSTT1 null-null genotypes. We hypothesize that there will be a 30% increase in urinary NNAL plus NNAL-Gluc, and a similar magnitude of reduction in urinary hydroxy acid and keto acid, a-hydroxylation metabolites of NNK, among PEITC treated subjects. The secondary aims of the proposed study are to (1) examine the differential effect of PEITC supplementation on NNK metabolism and PEITC excretion between the null and non-null GSTM1/GSTT1 genotypes, and (2) to assess the effect PEITC supplementation (at 40 mg/day for 12 months) on reduction of cell proliferation (Ki-67) and induction of apoptosis (caspase-3 and TUNEL) in bronchial epithelia of current smokers. This is the first randomized intervention trial to assess the chemopreventive effect of PEITC on lung cancer development in humans. PUBLIC HEALTH RELEVANCE: Despite anti-smoking campaigns over the past 40 years, approximately 45 million adult Americans are currently smoking cigarettes and other tobacco products. Smoking-related lung cancer is the leading cause of cancer death in the United States and worldwide. The proposed study is to examine the effect of a dietary compound, 2-phenethyl isothiocyanate, on lung cancer protection in smokers. Supportive findings of this study will lead to the development of this compound as a dietary supplement for the protection against lung cancer development in smokers. The major strengths include the need for a randomized, placebo-controlled trial of PEITC, the qualification of the investigators, and the feasibility of the proposed studies.